In 2020, researchers showed for the first time in a laboratory setting that a molecule found in green tea can block the signals that trigger irregular heartbeats.
The molecule is called Epigallocatechin-3-Gallate (EGCG). It is an antioxidant produced as a secondary metabolite, which means it is produced by the plant but is not directly needed for the plant’s normal growth and metabolism. Instead, such compounds often help the plant defend itself against damage by, for example, herbivores.
A patient is said to suffer from cardiac arrhythmia when their heart does not beat to a regular rhythm. Irregular heartbeats can happen when too many sodium atoms (Na+) enter the heart cells, because sodium atoms produce the electric signals that trigger heartbeats.
A special channel called Nav1.5 transports sodium atoms in and out of the heart. In patients with cardiac arrhythmia, the channel brings in too many sodium atoms, so researchers are looking for ways to block this channel.
Researchers wanted to know how the EGCG might interact with this sodium channel, to see if it can be used to block the sodium signals that trigger irregular heartbeats.
In a laboratory, the researchers first built sodium channels in heart cells by introducing sodium channel genes (a blueprint in the form of DNA) into the cells.
Next, they added EGCG to the cells and looked at how electric signals changed cells when different amounts of EGCG was added.
They also used a drug that is known to interact with open sodium channels to check if EGCG could close the channel. If EGCG did close the channel, this drug would have no effect because it doesn’t interact with closed sodium channels.
Lastly, they used modelling to see how EGCG moves in the cell membrane, which is where the sodium channel connects the inside of the cell to the outside of the cell to bring in sodium.
They found that indeed EGCG closes the channel and that the channel takes time to re-open. The more EGCG there is, the less electric signal there is in the heart cells.
They found that EGCG prefers to interact with the closed channel, and that the drug meant to block the open channel did not work because the channel was already closed by EGCG.
Their modelling showed that EGCG is found in the cell membrane, which might explain how it could interact with the channel there.
Previous research suggested that green tea extracts such as EGCG may protect the heart and may reduce the risk of heart disease. Here, researchers report a possible mechanism for how it might offer that protection, namely by blocking sodium channels.
The authors said the next step towards a potential therapy for patients with cardiac arrhythmia would be to find out how exactly EGCG is able to close the sodium channels.
Moroccan scientists contributed to this research.
Abstract
Epigallocatechin-3-Gallate (EGCG) has been extensively studied for its protective effect against cardiovascular disorders. This effect has been attributed to its action on multiple molecular pathways and transmembrane proteins, including the cardiac Nav1.5 channels, which are inhibited in a dose-dependent manner. However, the molecular mechanism underlying this effect remains to be unveiled. To this aim, we have characterized the EGCG effect on Nav1.5 using electrophysiology and molecular dynamics (MD) simulations. EGCG superfusion induced a dose-dependent inhibition of Nav1.5 expressed in tsA201 cells, negatively shifted the steady-state inactivation curve, slowed the inactivation kinetics, and delayed the recovery from fast inactivation. However, EGCG had no effect on the voltage-dependence of activation and showed little use-dependent block on Nav1.5. Finally, MD simulations suggested that EGCG does not preferentially stay in the center of the bilayer, but that it spontaneously relocates to the membrane headgroup region. Moreover, no sign of spontaneous crossing from one leaflet to the other was observed, indicating a relatively large free energy barrier associated with EGCG transport across the membrane. These results indicate that EGCG may exert its biophysical effect via access to its binding site through the cell membrane or via a bilayer-mediated mechanism.
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